Pathophysiology of Asthma: Inflammation, Mediators, and Mechanisms

Br J Clin Pharmacol 1996; 42: 3–10
Pathophysiology of asthma
PETER J. BARNES
Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College, London, UK
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Our understanding of asthma and its therapy has changed markedly over the
last few years, particularly with the application of molecular and cell biology
and the discovery of new and more specific pharmacological tools.
Many inflammatory cells participate in the inflammatory process in asthma
and mediate a complex mixture of mediators. Cytokines are of particular
importance as mediators of chronic inflammation and the means by which
cytokines amplify and perpetuate the inflammatory process is now emerging.
Airway epithelial cells may be a particularly important source of cytokines
and other mediators, such as nitric oxide and endothelin, and may be a major
target cell for inhaled steroids, which are the most effective therapy for asthma
currently available.
The inflammatory process in asthma results not only in bronchoconstriction,
but also plasma exudation, the activation of neural mechanisms, mucus
secretion. The chronic inflammation may lead to structural changes, including
an increase in airway smooth muscle and fibrosis, that are essentially
irreversible. There is increasing evidence that transcription factors, such as
NF-kB, play a pivotal role in the expression of inflammatory genes in asthma
and may be the major molecular target for glucocorticoids.
Keywords asthma
inflammation
inflammatory mediators
eosinophils
T-lymphocytes epithelial cells neuropeptides transcription factors
Introduction
used to treat asthma have provided important insights
into disease mechanisms. Colin Dollery has made
important contributions to this field in pioneering the
clinical pharmacology approach, leading to greater
understanding of adrenergic and neural mechanisms of
asthma and the role of inflammatory mediators, such as
leukotrienes and prostaglandins.
Our views on asthma have changed in the last decade,
with the recognition that chronic inflammation underlies
the clinical syndrome. In the past it was assumed that
the basic defect in asthma lay in abnormal contractility
of airway smooth muscle, giving rise to variable airflow
obstruction, and the common symptoms of intermittent
wheeze and shortness of breath. However studies of
airway smooth muscle from asthmatic patients have
shown no convincing evidence for increased contractile
responses to spasmogens such as histamine in vitro,
indicating that asthmatic airway smooth muscle is not
Asthma is one of the commonest diseases in industrialized countries and there is convincing evidence to
suggest that its prevalence and morbidity are increasing,
despite better recognition and increased prescriptions
for anti-asthma therapy. It is somewhat paradoxical
that the morbidity and mortality of asthma should be
increasing at a time when there is increased understanding of the pathophysiology of asthma and when effective
therapies are available; it points to the need for even
better understanding of the underlying mechanisms
involved in asthma and elucidation of the mode of
action of currently available anti-asthma therapies.
Clinical pharmacology has made important contributions to our understanding of asthma, since drugs
such as mediator antagonists have elucidated the
underlying inflammatory mechanisms and the drugs
Correspondence: Professor P. J. Barnes, Department of Thoracic Medicine, National Heart and Lung Institute, Imperial College,
Dovehouse Street, London SW3 6LY, UK
© 1996 Blackwell Science Ltd
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P. J. Barnes
fundamentally abnormal and suggesting that it is the
control of airway calibre in vivo which is abnormal.
For many years it has been assumed that mast cells
play a critical role in asthma and that mast cell
mediators produce the pathophysiology of asthma.
More recently it has become clear that many different
inflammatory cells are activated in asthmatic airways,
and that these cells produce a variety of mediators
which act in a complex manner on target cells of the
airways to produce the abnormal pathophysiological
features typical of asthma. Recent research has established that asthma, even in its mildest clinical forms,
involves a special type of inflammation in the airways.
asthma is a chronic inflammatory disease, with inflammation persisting over many years in most patients.
Superimposed on this chronic inflammatory state are
acute inflammatory episodes which correspond to
exacerbations of asthma. It is clearly important to
understand the mechanisms of acute and chronic
inflammation in asthmatic airways and to investigate
the long-term consequences of this chronic inflammation
on airway function. It is also important to consider the
effects of therapy on the inflammatory process.
Inflammatory cells
Asthma as an inflammatory disease
It had been recognised for many years that patients
who die of asthma attacks have grossly inflamed
airways. The airway lumen is occluded by a tenacious
mucus plug composed of plasma proteins exuded from
airway vessels and mucus glycoproteins secreted from
surface epithelial cells. The airway wall is oedematous
and infiltrated with inflammatory cells, which are
predominantly eosinophils and lymphocytes. The airway
epithelium is invariably shed in a patchy manner and
clumps of epithelial cells are found in the airway lumen.
Occasionally there have been opportunities to examine
the airways of asthmatic patients who die accidentally
and similar though less marked inflammatory changes
have been observed [ 1]. More recently it has been
possible to examine the airways of asthmatic patients
by fibreoptic and rigid bronchoscopy, by bronchial
biopsy and by bronchoalveolar lavage (BAL ). Direct
bronchoscopy reveals that the airways of asthmatic
patients are often reddened and swollen, indicating
acute inflammation. Lavage has revealed an increase in
the numbers of lymphocytes, mast cells and eosinophils
and evidence for activation of macrophages in comparison with non-asthmatic controls. Biopsies have revealed
evidence for increased numbers and activation of mast
cells, macrophages, eosinophils and T-lymphocytes [2].
These changes are found even in patients with mild
asthma who have few symptoms, and this suggests that
asthma is an inflammatory condition of the airways.
The relationship between inflammation and clinical
symptoms of asthma is not clear. There is evidence that
the degree of inflammation is related to airway hyperresponsiveness (AHR), as measured by histamine or
methacholine challenge. Increased airway responsiveness
is an exaggerated airway narrowing in response to many
stimuli which is characteristic of asthma and the degree
of AHR relates to asthma symptoms. Inflammation of
the airways may increase airway responsiveness which
thereby allows triggers which would not narrow the
airways to do so. But inflammation may also directly
lead to an increase in asthma symptoms, such as cough
and chest tightness, by activation of airway sensory
nerve endings.
Although most attention has been focused on the
acute inflammatory changes seen in asthmatic airways,
Many different inflammatory cells are involved in
asthma, although the precise role of each cell type is
not yet certain [3, 4]. It is evident that no single
inflammatory cell is able to account for the complex
pathophysiology of asthma, but some cells are predominant in asthmatic inflammation.
Mast cells are clearly important in initiating the acute
responses to allergen and probably to other indirect
stimuli, such as exercise and hyperventilation (via
osmolality or thermal changes) and fog. However there
are questions about the role of mast cells in more
chronic inflammatory events, and it seems more probable
that other cells such as macrophages, eosinophils and
T-lymphocytes are more important in the chronic
inflammatory process, including AHR.
Macrophages, which are derived from blood monocytes, may traffic into the airways in asthma and may
be activated by allergen via low affinity IgE receptors
[5 ]. The enormous repertoire of macrophages allows
these cells to produce many different products, including
a large variety of cytokines which may orchestrate the
inflammatory response. Macrophages therefore have the
capacity to initiate a particular type of inflammatory
response via the release of a certain pattern of cytokines.
Macrophages may both increase and decrease inflammation, depending on the stimulus. Alveolar macrophages normally have a suppressive effect on lymphocyte
function, but this may be impaired in asthma after
allergen exposure [6]. Macrophages may therefore play
an important anti-inflammatory role, preventing the
development of allergic inflammation. Macrophages
may also act as antigen-presenting cells which process
allergen for presentation to T-lymphocytes, although
alveolar macrophages are far less effective in this respect
than macrophages from other sites, such as the peritoneum [ 7]. By contrast dendritic cells which are
specialised macrophage-like cells in the airway epithelium, are very effective antigen-presenting cells [7 ],
and may therefore play a very important role in the
initiation of allergen-induced responses in asthma.
Eosinophil infiltration is a characteristic feature of
asthmatic airways and differentiates asthma from other
inflammatory conditions of the airway. Indeed, asthma
might more accurately be termed ‘chronic eosinophilic
bronchitis’ (a term first used in 1916!). Allergen inhalation
results in a marked increase in eosinophils in bronchoalveolar lavage fluid at the time of the late reaction, and
© 1996 Blackwell Science Ltd
British Journal of Clinical Pharmacology 42, 3–10
Pathophysiology of asthma
there is a close relationship between eosinophil counts
in peripheral blood or bronchial lavage and AHR.
Eosinophils were originally viewed as beneficial cells in
asthma, as they have the capacity to inactivate histamine
and leukotrienes, but it now seems more likely that they
may play a damaging role, and may be linked to the
development of airway hyperresponsiveness through the
release of basic proteins and oxygen-derived freeradicals
[8].
An important area of research is now concerned with
the mechanisms involved in recruitment of eosinophils
into asthmatic airways. Eosinophils are derived from
bone marrow precursors. After allergen challenge eosinophils appear in BAL fluid during the late response, and
this is associated with a decrease in peripheral eosinophil
counts and with the appearance of eosinophil progenitors in the circulation. The signal for increased eosinophil
production is presumably derived from the inflamed
airway. Eosinophil recruitment initially involves
adhesion of eosinophils to vascular endothelial cells in
the airway circulation, their migration into the submucosa and their subsequent activation. The role of
individual adhesion molecules, cytokines and mediators
in orchestrating these responses has yet to be clarified.
Adhesion of eosinophils involves the expression of
specific glycoprotein molecules on the surface of eosinophils (integrins) and their expression of such molecules
as intercellular adhesion molecule-1 (ICAM-1 ) on
vascular endothelial cells. An antibody directed at
ICAM-1 markedly inhibits eosinophil accumulation in
the airways after allergen exposure and also blocks the
accompanying hyperresponsiveness [9]. However
ICAM-1 is not selective for eosinophils and cannot
account for the selective recruitment of eosinophils in
allergic inflammation. The adhesion molecules VLA4
expressed on eosinophils and vascular cell adhesion
molecule-1 (VCAM-1) appear to be more selective for
eosinophils [10 ] and interleukin-4 (IL-4) increases the
expression of VCAM-1 on endothelial cells [11].
Eosinophil migration may be due to the effects of
platelet anticoating factor (PAF), which is selectively
chemoattractant to eosinophils [ 12], and to the effects
of cytokines such as GM-CSF, IL-3 and IL-5 [13].
These cytokines may be very important for the survival
of eosinophils in the airways and may ‘prime’ eosinophils
to exhibit enhanced responsiveness. Eosinophils from
asthmatic patients show greatly exaggerated responses
to PAF and phorbol esters, than eosinophils from atopic
non-asthmatic individuals [ 14] and this is further
increased by allergen challenge [15 ], suggesting that
they may have been primed by exposure to cytokines in
the circulation. There are several mediators involved
in the migration of eosinophils from the circulation to
the surface of the airway. The most potent and selective agents appear to be chemokines, such as RANTES,
that is expressed in epithelial cells [16 ], and eotaxin [ 17 ].
The role of neutrophils in human asthma is less clear.
Neutrophils are found in the airways of chronic
bronchitics and patients with bronchiectasis who do not
have the degree of AHR found in asthma, but there is
increasing evidence that neutrophils may be important
in acute exacerbations of asthma.
© 1996 Blackwell Science Ltd
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T-lymphocytes play a very important role in
co-ordinating the inflammatory response in asthma
through the release of specific patterns of cytokines,
resulting in the recruitment and survival of eosinophils
and in the maintenance of mast cells in the airways.
T-lymphocytes are coded to express a distinctive pattern
of cytokines, which may be similar to that described in
the murine Th2 type of T-lymphocytes, which characteristically expresses IL-3, IL-4 and IL-5 [18 ]. This
programming of T-lymphocytes is presumably due to
antigen presenting cells such as dendritic cells, which
may migrate from the epithelium to regional lymph
nodes or which interact with lymphocytes resident in
the airway mucosa.
Epithelial cells
Epithelial cells also produce inflammatory mediators,
such as endothelins, proinflammatory cytokines, chemokines and growth factors [19]. Epithelial cells may
play a key role in translating inhaled environmental
signals into an airway inflammatory response and are
probably the main target cell for inhaled glucocorticoids.
Inflammatory mediators
Many different mediators have been implicated in
asthma and they may have a variety of effects on the
airways which could account for the pathological
features of asthma [ 20, 21]. Mediators such as
histamine, prostaglandins and leukotrienes contract
airway smooth muscle, increase microvascular leakage,
increase airway mucus secretion and attract other
inflammatory cells. Because each mediator has many
effects the role of individual mediators in the
pathophysiology of asthma is not yet clear. Indeed the
multiplicity of mediators makes it unlikely that
antagonising a single mediator will have a major
impact in clinical asthma.
The cysteinyl-leukotrienes LTC , LTD and LTE are
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potent constrictors of human airways and have been
reported to increase AHR and may play an important
role in asthma [22 ]. The recent development of potent
specific leukotriene antagonists has made it possible to
evaluate the role of these mediators in asthma. Potent
LTD antagonists protect (by about 50%) against
4
exercise- [ 23] and allergen-induced bronchoconstriction
[24 ], suggesting that leukotrienes contribute to bronchoconstrictor responses. Chronic treatment with leukotriene antagonists improve lung function and symptoms
in asthmatic patients, although the degree of improvement is modest compared with what would be expected
of an inhaled glucocorticoid [25 ]. The role of leukotrienes in chronic asthma remains to be defined and
several clinical trials with potent antagonists are currently underway.
A mediator which has attracted considerable attention
recently is PAF, since it mimics many of the features of
British Journal of Clinical Pharmacology 42, 3–10
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P. J. Barnes
asthma, including AHR [12]. Although PAF appears
to be produced by the inflammatory cells involved in
asthmatic inflammation and mimics many of the
pathophysiological features of asthma, its role in asthma
will only become apparent with the use of potent and
specific antagonists. Initial results with potent PAF
antagonists such as apafant (WEB 2086 ) and modipafant
in chronic asthma have been disappointing, however
[26, 27 ].
Nitric oxide
Nitric oxide (NO) is produced by several cells in the
airway by NO synthases (NOS) [32 ]. An inducible
form of the enzyme (iNOS) is expressed in epithelial
cells of asthmatic patients [ 33] and can be induced by
cytokines in airway epithelial cells [ 34]. This may
account for the increased concentration of NO in the
exhaled air of asthmatic patients [35 ]. NO itself is a
potent vasodilator and this may increase plasma exudation in the airways; it may also amplify the
Th2-lymphocyte mediated response [36].
Cytokines
Cytokines are increasingly recognised to be important
in chronic inflammation and play a critical role in
orchestrating the type of inflammatory response. Many
inflammatory cells (macrophages, mast cells, eosinophils
and lymphocytes) are capable of synthesising and
releasing these proteins, and structural cells such as
epithelial cells and endothelial cells may also release a
variety of cytokines and may therefore participate in
the chronic inflammatory response [13]. While inflammatory mediators like histamine and leukotrienes may
be important in the acute and subacute inflammatory
responses and in exacerbations of asthma, it is likely
that cytokines play a dominant role in chronic inflammation. Almost every cell is capable of producing
cytokines under certain conditions. Research in this area
is hampered by a lack of specific antagonists, although
important observations have been made using specific
neutralising antibodies. The cytokines which appear to
be of particular importance in asthma include the
lymphokines secreted by T-lymphocytes: IL-3, which is
important for the survival of mast cells in tissues, IL-4
which is critical in switching B-lymphocytes to produce
IgE and for expression of VCAM-1 on endothelial cells,
IL-5 which is of critical importance in the differentiation,
survival and priming of eosinophils. There is evidence
for increased gene expression of IL-5 in lymphocytes in
bronchial biopsies of patients with symptomatic asthma
[28 ]. Other cytokines, such as IL-1, IL-6, tumour
necrosis factor-a (TNF-a) and GM-CSF are released
from a variety of cells, including macrophages and
epithelial cells, and may be important in amplifying the
inflammatory response. TNF-a may be an important
amplifying mediator in asthma and is produced in
increased amounts in asthmatic airways. Inhalation of
TNF-a increased airway responsiveness in normal
individuals [29].
Effects of inflammation
The chronic inflammatory response has several effects
on the target cells of the airways, resulting in the
characteristic pathophysiological changes associated
with asthma. Important advances have recently been
made in understanding these changes, although their
role in asthma symptoms is often not clear.
Airway epithelium
Airway epithelial shedding may be important in contributing to airway hyperresponsiveness and may explain
how several different mechanisms, such as ozone exposure, certain virus infections, chemical sensitisers and
allergen exposure, can lead to its development, since all
these stimuli may lead to epithelial disruption.
Epithelium may be shed as a consequence of inflammatory mediators, such as eosinophil basic proteins and
oxygen-derived free radicals, together with various
proteases released from inflammatory cells. Epithelial
cells are commonly found in clumps in the BAL or
sputum (Creola bodies) of asthmatics, suggesting that
there has been a loss of attachment to the basal layer
or basement membrane. Epithelial damage may contribute to AHR in a number of ways, including loss of its
barrier function to allow penetration of allergens, loss
of enzymes (such as neutral endopeptidase) which
normally degrade inflammatory mediators, loss of a
relaxant factor (so called epithelial-derived relaxant
factor), and exposure of sensory nerves which may lead
to reflex neural effects on the airway.
Subepithelial fibrosis
Endothelins
Endothelins are potent peptide mediators that are
potent vasoconstrictors and bronchoconstrictors [30].
They also induce airway smooth muscle cell proliferation
and fibrosis and may therefore play a role in the chronic
inflammation of asthma. There is evidence for increased
expression of endothelins in asthma, particularly in
airway epithelial cells [ 31].
An apparent increase in the basement membrane has
been described in fatal asthma, although similar changes
have been described in the airways in other conditions
[1 ]. Electron microscopy of bronchial biopsies in
asthmatic patients demonstrates that this thickening is
due to subepithelial fibrosis [ 2]. Type III and V collagen
appear to be laid down, and may be produced by
myofibroblasts which are situated under the epithelium.
The mechanism of fibrosis is not yet clear but several
cytokines, including TGFb and platelet derived growth
© 1996 Blackwell Science Ltd
British Journal of Clinical Pharmacology 42, 3–10
Pathophysiology of asthma
factor (PDGF) may be produced by epithelial cells or
macrophages in the inflamed airway [ 13].
Airway smooth muscle
There is still debate about the role of abnormalities in
airway smooth muscle in asthmatic airways. In vitro
airway smooth muscle from asthmatic patients usually
shows no increased responsiveness to spasmogens.
Reduced responsiveness to b-adrenoceptor agonists has
also been reported in post-mortem or surgically removed
bronchi from asthmatics, although the number of
b-receptors is not reduced, suggesting that b-receptors
have been uncoupled [37]. These abnormalities of airway
smooth muscle may be a reflection of the chronic
inflammatory process. For example the reduced
b-adrenergic responses in airway smooth muscle could be
due to phosphorylation of the stimulatory G-protein
coupling b-receptors to adenylyl cyclase, resulting from
the activation of protein kinase C by the stimulation of
airway smooth muscle cells by inflammatory mediators
[38].
In asthmatic airways there is also a characteristic
hypertrophy and hyperplasia of airway smooth muscle
[39 ], which is presumably the result of stimulation of
airway smooth muscle cells by various growth factors,
such as PDGF, or endothelin-1 released from inflammatory cells.
Vascular responses
Vasodilatation occurs in inflammation, yet little is
known about the role of the airway circulation in
asthma, partly because of the difficulties involved in
measuring airway blood flow. The bronchial circulation
may play an important role in regulating airway calibre,
since an increase in the vascular volume may contribute
to airway narrowing. Increased airway blood flow may
be important in removing inflammatory mediators from
the airway, and may play a role in the development of
exercise-induced asthma.
Plasma extravasation
Microvascular leakage is an essential component of the
inflammatory response and many of the inflammatory
mediators implicated in asthma produce this leakage
[20, 40, 41 ]. There is good evidence for microvascular
leakage in asthma and it may have several consequences
on airway function, including increased airway
secretions, impaired mucociliary clearance, formation of
new mediators from plasma precursors (such as kinins)
and mucosal oedema which may contribute to airway
narrowing and increased airway hyperresponsiveness.
Mucus hypersecretion
Mucus hypersecretion is a common inflammatory
response in secretory tissues. Increased mucus secretion
© 1996 Blackwell Science Ltd
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contributes to the viscid mucus plugs which occlude
asthmatic airways, particularly in fatal asthma. There is
evidence for hyperplasia of submucosal glands which
are confined to large airways and of increased numbers
of epithelial goblet cells. This increased secretory
response may be due to inflammatory mediators acting
on submucosal glands and due to stimulation of neural
elements. Little is understood about the control of
goblet cells, which are the main source of mucus in
peripheral airways, although recent studies investigating
the control of goblet cells in guinea pig airways suggest
that cholinergic, adrenergic and sensory neuropeptides
are important in stimulating secretion [ 42].
Neural effects
There has recently been a revival of interest in neural
mechanisms in asthma [43]. Autonomic nervous control
of the airways is complex, for in addition to classical
cholinergic and adrenergic mechanisms, non-adrenergic
non-cholinergic (NANC) nerves and several neuropeptides have been identified in the respiratory tract [44 ].
Several studies have investigated the possibility that
defects in autonomic control may contribute to airway
hyperresponsiveness and asthma, and abnormalities of
autonomic function, such as enhanced cholinergic and aadrenergic responses or reduced b-adrenergic responses,
have been proposed. Current thinking suggests that
these abnormalities are likely to be secondary to the
disease, rather than primary defects [43 ]. It is possible
that airway inflammation may interact with autonomic
control by several mechanisms.
Inflammatory mediators may act on various
pre-junctional receptors on airway nerves to modulate
the release of neurotransmitters [45 ]. Thus thromboxane and prostaglandin D (PGD ) facilitate the
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release of acetylcholine from cholinergic nerves in
canine airways, whereas histamine inhibits cholinergic
neurotransmission at both parasympathetic ganglia and
post-ganglionic nerves via H -receptors. Inflammatory
3
mediators may also activate sensory nerves, resulting
in reflex cholinergic bronchoconstriction or release of
inflammatory neuropeptides. Inflammatory products
may also sensitise sensory nerve endings in the airway
epithelium, so that the nerves become hyperalgesic.
Hyperalgesia and pain (dolor) are cardinal signs of
inflammation, and in the asthmatic airway may mediate
cough and dyspnoea, which are such characteristic
symptoms of asthma. The precise mechanisms
of hyperalgesia are not yet certain, but mediators
such as prostaglandins and certain cytokines may be
important.
Bronchodilator nerves which are non-adrenergic are
prominent in human airways, and it has been suggested
that these nerves may be defective in asthma [46 ]. In
animal airways vasoactive intestinal peptide (VIP) has
been shown to be a neurotransmitter of these nerves
and a striking absence of VIP-immunoreactive nerves
has been reported in the lungs from patients with severe
fatal asthma [ 47]. However it is likely that this loss of
British Journal of Clinical Pharmacology 42, 3–10
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P. J. Barnes
VIP immunoreactivity is due to degradation by tryptase
released from degranulating mast cells in the airways of
asthmatics [48 ]. In human airways the bronchodilator
neurotransmitter appears to be NO [49].
Airway nerves may also release neurotransmitters
which have inflammatory effects. Thus neuropeptides
such as substance P (SP), neurokinin A and calcitoningene related peptide may be released from sensitised
inflammatory nerves in the airways which increase and
extend the ongoing inflammatory response [50 ]. There
is evidence for an increase in SP-immunoreactive nerves
in airways of patients with severe asthma [51 ], which
may be due to proliferation of sensory nerves and
increased synthesis of sensory neuropeptides as a result
of nerve growth factors released during chronic inflammation. There may also be a reduction in the activity
of enzymes, such as neutral endopeptidase, which
degrade neuropeptides such as SP [ 52]. There is also
evidence for increased gene expression of the receptor
which mediates the inflammatory effects of SP [ 53].
Thus chronic asthma may be associated with increased
neurogenic inflammation, which may provide a mechanism for perpetuating the inflammatory response even in
the absence of initiating inflammatory stimuli.
asthmatic patients have airway inflammation which
leads to airway narrowing it would seem more appropriate to use anti-inflammatory treatment as first-line
therapy [58 ]. For patients with mild asthma sodium
cromoglycate or nedocromil sodium may be sufficient,
but for many patients with asthma inhaled corticosteroids will be needed. Inhaled glucocorticoids are highly
effective in controlling asthma and may work on many
aspects of the chronic inflammatory response [59 ]. By
contrast bronchodilators, such as b -adrenoceptor agon2
ists, may relieve the symptoms of asthma acutely, but
fail to control the underlying chronic inflammatory
response. Indeed there is evidence to suggest that regular
use of inhaled b -adrenoceptor agonists may even
2
increase AHR and chronic asthma symptoms [ 60]. It is
now recommended that they should be used only for
acute symptom control and that asthma should be
controlled primarily with inhaled anti-inflammatory
agents. It is hoped that the earlier use of inhaled steroids
may reduce the morbidity and mortality of asthma and
may also prevent the irreversible structural changes
which may underlie the gradual decline in lung function
seen in patients with poorly controlled asthma and there
is some evidence to support this [61 ].
References
Transcription factors
The chronic inflammation of asthma is due to increased
expression of multiple inflammatory proteins (MIP:
cytokines, enzymes, receptors, adhesion molecules). In
many cases these inflammatory proteins are induced by
transcription factors, DNA binding factors that increase
the transcription of selected target genes [54 ]. One
transcription factor that may play a critical role in
asthma is nuclear factor-kappa B (NF-kB) which can
be activated by multiple stimuli, including protein kinase
C activators, oxidants and proinflammatory cytokines
(such as IL-1b and TNF-a). NF-kB is the predominant
transcription regulating the expression of iNOS, the
inducible form of cyclooxygenase (COX-2 ), chemokines
(IL-8, RANTES, MIP-1a), proinflammatory cytokines
(TNF-a, GM-CSF) and adhesion molecules (ICAM-1,
VCAM-1) [55 ]. NF-kB in epithelial cells may play
a pivotal role in amplifying inflammation in diseases
such as asthma [56]. This is further supported by
studies showing that NF-kB is potently inhibited by
glucocorticoids [57].
Implications for therapy
The advances in our understanding of asthma have
important implications for the way in which asthma
therapy should be used. In the past asthma was treated
primarily with bronchodilators, which act predominantly by relaxing airway smooth muscle. However
since it is now apparent that even the mildest of
1 Dunnill MS. The pathology of asthma, with special
reference to the changes in the bronchial mucosa. J Clin
Pathol 1960; 13: 27–33.
2 Djukanovic R, Roche UR, Wilson JW, et al. Mucosal
inflammation in asthma. Am Rev Respir Dis 1990; 142:
434–457.
3 Barnes PJ. New concepts in the pathogenesis of bronchial
hyperresponsiveness and asthma. J Allergy Clin Immunol
1989; 83: 1013–1026.
4 Barnes PJ. New aspects of asthma. J Int Med 1992;
231: 453–461.
5 Lee TM, Lane SJ. The role of macrophages in the
mechanisms of airway inflammation in asthma. Am Rev
Respir Dis 1992; 145: S27–30.
6 Spiteri MA, Knight RA, Jeremy JY, Barnes PJ, Chung
KF. Alveolar macrophage-induced suppression of peripheral blood mononuclear cell responsiveness is reversed
by in vitro allergen exposure in bronchial asthma. Eur
Resp J 1994; 7: 1431–1438.
7 Holt PG. Regulation of antigen-presenting cell function(s)
in lung and airway tissues. Eur Respir J 1993; 6: 120–129.
8 Gleich GJ. The eosinophil and bronchial asthma: current
understanding. J Allergy Clin Immunol 1990; 85: 422–436.
9 Wegner CD, Gundel L, Reilly P, Haynes N, Letts LG,
Rothlein R. Intracellular adhesion molecule-1 (ICAM-1)
in the pathogenesis of asthma. Science 1990; 247: 456–459.
10 Pilewski JM, Albelda SM. Cell adhesion molecules in
asthma: homing, activation and airway remodelling. Am
J Respir Cell Mol Biol 1995; 12: 1–3.
11 Lamas AM, Mulroney CM, Schleimer RP. Studies of the
adhesive interaction between purified human eosinophils
and cultured vascular endothelial cells. J Immunol 1988;
140: 1500–1510.
12 Barnes PJ, Chung KF, Page CP. Platelet-activating factor
as a mediator of allergic disease. J Allergy Clin Immunol
1988; 81: 919–934.
© 1996 Blackwell Science Ltd
British Journal of Clinical Pharmacology 42, 3–10
Pathophysiology of asthma
13 Barnes PJ. Cytokines as mediators of chronic asthma. Am
J Resp Crit Care Med 1994; 150: S42-S49.
14 Chanez P, Dent G, Yukawa T, Barnes PJ, Chung KF.
Generation of oxygen free radicals from blood eosinophils
from asthma patients after stimulation with PAF or
phorbol ester. Eur Respir J 1990; 3: 1002–1007.
15 Evans DJ, Lindsay MA, O’Connor BJ, Barnes PJ. Priming
of circulating human eosinophils following exposure to
allergen challenge. Eur Respir J 1996; (in press).
16 Kwon OJ, Jose PJ, Robbins RA, Schall TJ, Williams TJ,
Barnes PJ. Glucocorticoid inhibition of RANTES
expression in human lung epithelial cells. Am J Respir Cell
Mol Biol 1995; 12: 488–496.
17 Jose PJ, Griffiths-Johnson DA, Collins PD, et al. Eotaxin:
a potent eosinophil chemoattractant cytokine detected in
a guinea pig model of allergic airways inflammation. J Exp
Med 1994; 179: 881–887.
18 Kay AB. Asthma and inflammation. J Allergy Clin Immunol
1991; 87: 893–913.
19 Devalia JL, Davies RJ. Airway epithelial cells and
mediators of inflammation. Resp Med 1993; 6: 405–408.
20 Barnes PJ, Chung KF, Page CP. Inflammatory mediators
and asthma. Pharmacol Rev 1988; 40: 49–84.
21 Barnes PJ, Chung KF, Page CP. Inflammatory mediators
and asthma. Pharmacol Rev 1996; (in press).
22 Arm JP, Lee TH. Sulphidopeptide leukotrienes in asthma.
Clin Sci 1993; 84: 501–510.
23 Manning PJ, Watson RM, Margolskee, Williams VC,
Schwartz JI, O’Byrne PM. Inhibition of exercise-induced
bronchoconstriction by MK-571,a potent leukotriene D 4
receptor antagonist. New Engl J Med 1990; 323: 1736–1739.
24 Taylor IK, O’Shaughnessy KM, Fuller RW, Dollery CT.
Effect of cysteinyl-leukotriene receptor antagonist ICI
204,219 on allergen-induced bronchoconstriction and
airway hyperreactivity in atopic subjects. L ancet 1991;
337: 690–694.
25 Spector SL, Smith LJ, Glass M. Effects of 6 weeks of
therapy with oral doses of ICI 204,219, a leukotriene D
4
receptor antagonist in subjects with bronchial asthma. Am
J Resp Crit Care Med 1994; 150: 618–623.
26 Spence DPS, Johnston SL, Calverley PMA, et al. The
effect of the orally active platelet-activating factor antagonist WEB 2086 in the treatment of asthma. Am J Resp Crit
Care Med 1994; 149: 1142–1148.
27 Kuitert LM, Angus RM, Barnes NC, et al. The effect of a
novel potent PAF antagonist, modipafant, in chronic
asthma. Am J Respir Crit Care Med 1995; 151: 1331–1335.
28 Hamid Q, Azzawi M, Sun Ying, et al. Expression of mRNA
for interleukin-5 in mucosal bronchial biopsies from
asthma. J Clin Invest 1991; 87: 1541–1549.
29 Thomas PS, Yates DH, Barnes PJ. Tumor necrosis factora increases airway responsiveness and sputum neutrophils
in normal human subjects. Am J Respir Crit Care Med
1995; 152: 76–80.
30 Barnes PJ. Endothelins and pulmonary diseases. J Appl
Physiol 1994; 77: 1051–1059.
31 Springall DR, Howarth PH, Counihan H, Djukanovic R,
Holgate ST, Polak JM. Endothelin immunoreactivity of
airway epithelium in asthmatic patients. L ancet 1991;
337: 697–701.
32 Barnes PJ. Nitric oxide and airway disease. Ann Med 1995;
27: 91–97.
33 Hamid Q, Springall DR, Riveros-Moreno V, et al.
Induction of nitric oxide synthase in asthma. L ancet 1993;
342: 1510–1513.
34 Robbins RA, Barnes PJ, Springall DR, et al. Expression of
inducible nitric oxide synthase in human bronchial epi© 1996 Blackwell Science Ltd
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thelial cells. Biochem Biophys Res Commun 1994; 203:
209–218.
35 Kharitonov SA, Yates D, Robbins RA, Logan-Sinclair R,
Shinebourne E, Barnes PJ. Increased nitric oxide in exhaled
air of asthmatic patients. L ancet 1994; 343: 133–135.
36 Barnes PJ, Liew FY. Nitric oxide and asthmatic inflammation. Immunol T oday 1995; 16: 128–130.
37 Bai TR, Mak JCW, Barnes PJ. A comparison of betaadrenergic receptors and in vitro relaxant responses to
isoproterenol in asthmatic airway smooth muscle. Am
J Respir Cell Mol Biol 1992; 6: 647–651.
38 Grandordy BM, Mak JCW, Barnes PJ. Modulation of
airway smooth muscle b-adrenoceptor function by a
muscarinic agonist. L ife Sci 1994; 54: 185–191.
39 Ebina M, Yaegashi H, Chiba R, Takahashi T, Motomiya
M, Tanemura M. Hyperreactive site in the airway tree of
asthmatic patients recoded by thickening of bronchial
muscles: a morphometric study. Am Rev Respir Dis 1990;
141: 1327–1332.
40 Persson CGA. Plasma exudation and asthma. L ung 1988;
166: 1–23.
41 Chung KF, Rogers DF, Barnes PJ, Evans TW. The role
of increased airway microvascular permeability and plasma
exudation in asthma. Eur Respir J 1990; 3: 329–337.
42 Kuo H, Rhode JAL, Tokuyama K, Barnes PJ, Rogers DF.
Capsaicin and sensory neuropeptide stimulation of goblet
cell secretion in guinea pig trachea. J Physiol 1990;
431: 629–641.
43 Barnes PJ. Is asthma a nervous disease? The Parker B
Francis Lecture. Chest 1995; 107: 119S-124S.
44 Barnes PJ, Baraniuk J, Belvisi MG. Neuropeptides in the
respiratory tract. Am Rev Respir Dis 1991; 144: 1187–1198,
1391–1399.
45 Barnes PJ. Modulation of neurotransmission in airways.
Physiol Rev 1992; 72: 699–729.
46 Lammers JWJ, Barnes PJ, Chung KF. Non-adrenergic,
non-cholinergic airway inhibitory nerves. Eur Respir J
1992; 5: 239–246.
47 Ollerenshaw S, Jarvis D, Woolcock A, Sullivan C, Scheibner
T. Absence of immunoreactive vasoactive intestinal polypeptide in tissue from the lungs of patients with asthma.
N Engl J Med 1989; 320: 1244–1248.
48 Barnes PJ. Vasoactive intestinal peptide and asthma. N
Engl J Med 1989; 321: 1128–1129.
49 Belvisi MG, Stretton CD, Barnes PJ. Nitric oxide is the
endogenous neurotransmitter of bronchodilator nerves in
human airways. Eur J Pharmacol 1992; 210: 221–222.
50 Barnes PJ. Sensory nerves, neuropeptides and asthma. Ann
NY Acad Sci 1991; 629: 359–370.
51 Ollerenshaw SL, Jarvis D, Sullivan CE, Woolcock
AJ. Substance P immunoreactive nerves in airways from
asthmatics and non-asthmatics. Eur Respir J 1991; 4:
673–682.
52 Nadel JA. Neutral endopeptidase modulates neurogenic
inflammation. Eur Respir J 1991; 4: 745–754.
53 Adcock IM, Peters M, Gelder C, Shirasaki H, Brown CR,
Barnes PJ. Increased tachykinin receptor gene expression
in asthmatic lung and its modulation by steroids. J Mol
Endocrinol 1993; 11: 1–7.
54 Barnes PJ, Adcock IM. Transcription factors in asthma.
Clin Exp Allergy 1995; 27 (Suppl 2 ): 46–49.
55 Siebenlist U, Franzuso G, Brown R. Structure, regulation
and function of NF-kB. Ann Rev Cell Biol 1994; 10:
405–455.
56 Barnes PJ, Karin M. NF-kappa B: pivotal role in chronic
inflammation. N Engl J Med 1996; (in press).
57 Barnes PJ, Adcock IM. Anti-inflammatory actions of
British Journal of Clinical Pharmacology 42, 3–10
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P. J. Barnes
steroids: molecular mechanisms. T rends Pharmacol Sci
1993; 14: 436–441.
58 Barnes PJ. A new approach to asthma therapy. N Engl
J Med 1989; 321: 1517–1527.
59 Barnes PJ. Inhaled glucocorticoids for asthma. N Engl
J Med 1995; 332: 868–875.
60 Barnes PJ, Chung KF. Questions about inhaled b -agonists
2
in asthma. T rends Pharmacol Sci 1992; 13: 20–23.
61 Haahtela T, Järvinsen M, Kava T, et al. Effects of reducing
or discontinuing inhaled budesonide in patients with mild
asthma. N Engl J Med 1994; 331: 700–705.
© 1996 Blackwell Science Ltd
British Journal of Clinical Pharmacology 42, 3–10